Controlled release refers to the release of the therapeutically active agent from a composition or dosage form in which the agent is released according to a desired profile over an extended period of time. Controlled release profiles include, for example, sustained release, prolonged release, pulsatile release, and delayed release profiles. In contrast to immediate release compositions, controlled release compositions allow delivery of an agent to a subject over an extended period of time according to predetermined profile. Such release rates can provide therapeutically effective levels of an agent for an extended period of time and thereby provide a longer period of pharmacological or diagnostic response as compared to conventional rapid release dosage forms. Such longer periods of response provide for many inherent benefits that are not achieved with the corresponding short acting, immediate release preparations. For example, in the treatment of chronic pain, controlled release formulations are often highly preferred over conventional short-acting formulations.
Controlled release pharmaceutical compositions and dosage forms are designed to improve the delivery profile of agents, such as drugs, medicaments, active agents, diagnostic agents, or any substance to be internally administered to an animal, including humans. A controlled release composition is typically used to improve the effects of administered substances by optimizing the kinetics of delivery, thereby increasing bio-availability, convenience, and patient compliance, as well as minimizing side effects associated with inappropriate immediate release rates such as high initial release rate and, if undesired, uneven blood or tissue levels.
Lamotrigine, an antiepileptic drug of the phenyltriazine class is chemically unrelated to existing antiepileptic drug. Its chemical name is 3,5-diamino-6(2,3-dichlorophenyl)-1,2,4-triazine, its molecular formula is C9H7N5Cl2. It is disclosed in EP-A-0021121, which is incorporated by reference.
Lamotrigine has been used to treat over a million patients worldwide, including about 4000 adults and over 1000 children in clinical trials, Extensive experience with lamotrigine has indicated that it may be effective when other anticonvulsant drugs have failed. It is a valuable broad-spectrum drug that is well tolerated and has few adverse effects apart from skin rash (Besag FMC, CNS Drugs 2000). Pharmacokinetically, the plasma concentrations of lamotrigine vary linearly with the dose (Ramsay RE, 1991).
Over the range 50 to 400 mg as a single dose, Cmax increases proportionately from 0.58 to 4.63 μg/ml, as does the AUC (29.9 to 211.9 mg/L.h). Acute and chronic studies in humans have suggested that lamotrigine levels of 1-3 μg/ml are effective in controlling seizures (Betts et al, 1991). Adverse events associated with lamotrigine are typical of antiepileptic drugs, namely dizziness, ataxia, diplopia, somnolence, headache, and asthenia. The incidence of such side effects is around 10% (Ramsay RE, 1991), Overall, 8.6% of patients were removed from clinical trials because of adverse experiences that included, in addition to rash, nausea/vomiting and intolerable episodes of the CNS-related events (Ramsay RE, 1991; Goa K L et al, 1993).
Neurological side effects are normally seen at higher plasma concentrations (which are most likely to occur at peak plasma concentrations). During the first 18 weeks of lamotrigine treatment 16.7% of patients reported nausea and vomiting at a mean concentration of 6.00 to 7.99 μg/ml and 100% reporting headache and ataxia at >10 μg/ml (Goa K L et al, 1993). Similarly, Binnie et al., (1987) reported side effects only in patients with levels above 3 μg/ml.
Dose reduction and slow dosage escalation are two techniques to overcome these peak time side effects (Binnie et al, 1987). The present invention will reduce these side effects by controlling the Cmax of lamotrigine by the use of a novel controlled release formulation of lamotrigine. It will also maintain the steady state concentration with little fluctuations. The reduced incidence of these neurological side effects will improve patient compliance with the therapy.
Serious skin reactions (including Steven Johnson Syndrome and Toxic Epidermal Necrolysis) occurring in patients taking lamotrigine were highlighted by the Committee of Safety Medicine (CSM) in 1997 and have subsequently been discussed in the literature (Mitchell P, 1997; Anon., Drug and Therapy Perspectives, 1998). Rash, which has occurred in 10% of patients in placebo-controlled trials has led to discontinuation of therapy in 1% of patients (most common cause of discontinuation) (Besag FMC, CNS Drugs 2000). Skin reactions such as Stevens Johnson Syndrome are potentially fatal and have an incidence of 1 in 1000 person-years in adults. The incidence is higher in children. Risk factors for skin reactions include high plasma concentration, concomitant sodium valproate therapy (Valproate reduces the hepatic clearance of lamotrigine thereby increasing plasma concentrations of the drug by approximately two fold for a given dose), a high initial dose of lamotrigine and rapid dose escalation (Mitchell P, 1997; Anon., Current Problems in Pharmacovigilance).
There is some preliminary data that shows that slow dosage escalation or titration when initiating therapy may lessen the likelihood of development of severe rash (Ramsay RE, 1991). Controlled release lamotrigine, which is designed to avoid excessive Cmax levels, will produce lower plasma concentrations which are reached over a longer period of time and will reduce the incidence of this troublesome side effect of lamotrigine. Further, the controlled release formulation will be much safer to use with concomitantly administered drugs such as phenytoin, carbamazepine, sodium valproate etc.
Presently lamotrigine is prescribed in conventional tablets or dispersible/chewable tablet form in doses ranging from 25 to 600 mg/day, once a day or two divided doses. Immediate release dosage forms provide rapid dissolution results with a rapid increase in blood plasma levels after each dosing, which causes adverse effects. The reasons for giving divided doses of lamotrigine is to prevent very high concentrations in the plasma, which can occur with single daily dose of conventional formulation.
It is a known fact that frequent dosing results in poor patient compliance resulting in an inadequate/sub-optimal therapeutic effect.
Peak trough fluctuations at steady state are reduced whenever one or more of the following occur:                Increase in half-life.        Shorter dosing interval        Reduced rate of absorption.        
The oral administration of solid dosage forms, for example tablets, capsules, often presents ingestion problems for the patient, especially in case of children or old people. In order to get around this problem other forms of pharmaceutical formulations are resorted to, for example chewable tablets, dispersible tablets and monodose sachets, the contents of which are to be dissolved or suspended in water and taken orally.
The problems inherent in the administration of divided doses of lamotrigine point to the desirability of providing a controlled release formulation of lamotrigine, which can be given once daily to improve the patient compliance, which can be taken without water or can be dispersed in water for the convenience of the patients and can provide an improved pharmacokinetic profile. Improved pharmacokinetic profile here means that the formulation will provide a more constant blood level of drug and will show less fluctuation between the maximum and minimum plasma drug concentration than once or repeated doses of regular/immediate release drug formulation containing equal amounts of active ingredients administered per day.
Formulations according to this aspect of the present invention are particularly useful in administration of medications to individuals who cannot or will not chew or swallow, such as debilitated patients, patients who have difficulty swallowing solids, and the elderly. Furthermore, the formulations according to the invention provide a further significant advantage with respect to tablet or simple capsule. People who need to swallow a tablet or a capsule under the above mentioned conditions may sometimes have to swallow the said tablet or capsule without water and that can be dangerous as the tablet or capsule can get into trachea i.e. respiratory site.
The prior art discloses many different types of multiple unit dosage forms. An example of a controlled release dosage form, which releases the active substance by diffusion through a membrane, is described in U.S. Pat. No. 4,927,640, i.e. a multiple unit system containing small inert cores with an active substance and a release controlling polymeric membrane. The mechanical properties of such multiple units formulated into tablets are reported in Pharmaceutical Research, 10 (1993), p. 274. There are examples in prior art which disclose that pellets may be formulated into tablets, there are no examples describing any compositions of such a tablet formulation or a technique to manufacture such a formulation comprising lamotrigine which is given once a day and provided improved pharmacokinetic profile.